This invention relates to novel derivatives of 1,5-dideoxy-1,5-imino-D-glucitol having chloro or bromo substituents at C-2, and, more particularly, to the chemical synthesis of these derivatives and intermediates therefor. These compounds are useful for inhibiting glycosidase enzymes such as, for example, .alpha.- and .beta.-glucosidases.
1,5-dideoxy-1,5-imino-D-glucitol (deoxynojirimycin or DNJ) and its N-alkyl and O-acylated derivatives are known inhibitors of glycosidase enzymes. They are also known to be inhibitors of viruses such as human immunodeficiency virus (HIV) or pro-drugs for such inhibitors. See, e.g., U.S. Pat. Nos. 4,849,430; 5,003,072; 5,030,638 and PCT Int'l. Appln. WO 87/03903. Several of these derivatives also are effective against other viruses such as HSV and CMV as disclosed in U.S. Pat. No. 4,957,926. In some cases antiviral activity is enhanced by combination of the DNJ derivative with other antiviral agents such as AZT as described in U.S. Pat. No. 5,011,829. Various of these DNJ derivative compounds are reported to be antihyperglycemics and similar such therapeutic agents for metabolic diseases based on their activity as glycosidase inhibitors. See, e.g., U.S. Pat. Nos. 4,182,763, 4,533,668 and 4,639,436. Various 2-fluoro derivatives of 1,5-dideoxy-1,5-imino-D-glucitol have been described as glycosidase inhibitors in U.S. Pat. No. 5,025,021.
Further background information on the conventional use of DNJ and various related compounds as inhibitors of oligosaccharide processing, protein glycosylation and glycoprotein processing can be had by reference to leading review articles such as Truscheit et al., Angew. Chem. Ind. Engl. 20, 744-761 (1981); Elbein, Crit. Rev. Biochem. 16, 21-49 (1984); Fuhrmann et al., Biochim. Biophys. Acta 825, 95-100 (1985); Fellows, Pestic. Sci. 17, 602-606 (1986); Datema et al., Pharmac. Ther. 33, 221-286 (1987); and references cited therein.
Notwithstanding the foregoing, the search continues for the discovery and novel synthesis of new and improved glycosidase inhibitors.